CONTINUOUS PROCESS FOR THE PRODUCTION OF BETA-KETO ESTERS BY CLAISEN CONDENSATION

PROCEDE CONTINU POUR LA PRODUCTION DE BETA-CETO ESTERS PAR CONDENSATION DE CLAISEN

English Abstract

The invention concerns a continuous process for the production of compounds having the general formula (6) comprising providing to a reaction zone a continuous stream of an alkyl acetate and a continuous stream of an alkali metal or alkaline earth metal amide base and contacting the continuous streams together in the reaction zone to yield an enolate compound, providing to the or a separate reaction zone a continuous stream of a compound of formula (5) and contacting the continuous stream of compound (5) with a continuous stream of the enolate in the or the separate reaction zone at a temperature above 20°C to yield an intermediate compound and treating the intermediate compound of formula (1) with an acid to yield the compound of formula (6).

French Abstract

L'invention concerne un procédé continu de fabrication de composés de formule générale (6) qui comprend l'introduction dans une zone de réaction d'un courant continu d'un acétate d'alkyle et d'un courant continu d'une base amide de métal alcalin ou de métal alcalino-terreux et la mise en contact des courants continus dans la zone de réaction pour obtenir un composé d'énolate, l'introduction dans la zone de réaction ou une zone de réaction distincte d'un courant continu d'un composé de formule (5), et la mise en contact du courant continu du composé (5) avec un courant continu de l'énolate (4) dans la zone de réaction ou une zone de réaction distincte à une température supérieure à 20 °C pour obtenir un composé intermédiaire, et le traitement du composé intermédiaire de formule (1) avec un acide pour obtenir le composé de formule (6).

Claims

CLAIMS
1. A continuous process for the production of compounds having the
general formula (6):
<IMG>
wherein:
R is a straight or branched chain alkyl group;
R1 is a straight or branched chain alkyl group substituted
with a nitrile group, a hydroxy group or a halogen atom;
R2 is a hydroxy group or a keto group; and
each R3 is, independently, hydrogen or a straight or
branched chain alkyl group,
the process comprising providing to a reaction zone a continuous
stream of a compound of formula (3):
<IMG>
wherein R and R3 are as previously defined and R4 is
hydrogen or has the general formula (7):
-16-

<IMG>
wherein R3 is as defined above
and a continuous stream of an alkali metal or alkaline earth metal
amide base, alkyl lithium or Grignard reagent; contacting the
continuous streams together in the reaction zone to yield the
enolate of formula (4):
<IMG>
wherein R and R3 are as previously defined, X is an alkali metal or
alkaline earth metal, and R5 is hydrogen or has the general
formula (8):
<IMG>
wherein R3 and X are as previously defined;
providing to the or a separate reaction zone a continuous stream
of a compound of formula (5):
<IMG>
-17-

wherein R and R1 are as previously defined or may together form
a ring structure, R6 is hydrogen, hydroxyl, alkoxyl or a keto group
and n is 0 or 1;
and contacting the continuous stream of compound (5) with a
continuous stream of the enolate (4) in the or the separate
reaction zone at a temperature above 20°C to yield a compound
of formula (1):
<IMG>
wherein R1, R and X are as previously defined, and treating the
compound of formula (1) with an acid to yield the compound of
formula (6).
2. A process according to claim 1 wherein the stoichiometric ratio of alkali
metal or alkaline earth metal amide base, alkyl lithium or a Grignard
reagent to compound (5) supplied to the and/or to the separate
reaction zone is less than about 4.5 : 1.
3. A process according to claim 1 or claim 2 wherein the steps of
providing to the reaction zone a continuous stream of a compound of
formula (3) and a continuous stream of an alkali metal or alkaline earth
-18-

metal amide base, alkyl lithium or Grignard reagent, and the steps of
providing to the or the separate reaction zone a continuous stream of a
compound of formula (5) are sequential steps.
4. A process according to any one of claims 1 to 3 wherein the
temperature at which compounds (4) and (5) are reacted together is
above 25°C.
5. A process according to claim 4 wherein the temperature at which
compounds (4) and (5) are reacted together is above 30°C.
6. A process according to any one of claims 1 to 5 wherein the residence
time of the contacted continuous streams of compounds (4) and (5) in
the or the separate reaction zone is less than about 5 minutes.
7. A process according to claim 6 wherein the residence time of the
contacted continuous streams of compounds (4) and (5) in the or the
separate reaction zone is less than about 1 minute.
8. A process according to claim 7 wherein the residence time of the
contacted continuous streams of compounds (4) and (5) in the or the
separate reaction zone is less than about 50 seconds.
-19-

9. A process according to claim 8 wherein the residence time of the
contacted continuous streams of compounds (4) and (5) in the or the
separate reaction zone is less than about 40 seconds.
10.A process according to any one of claims 1 to 9 wherein the residence
time of the contacted continuous streams of compound (3) and the
alkali metal or alkaline earth metal amide base, alkyl lithium or
Grignard reagent in the reaction zone is less than about 5 minutes.
11.A process according to any one of claims 1 to 10 wherein the enolate
compound is prepared from the reaction of compound (3) and the alkali
metal or alkaline earth metal amide base, alkyl lithium or Grignard
reagent in a first reaction zone, and the compound of formula (1) is
prepared from the reaction between compounds (4) and (5) in a
second reaction zone.
12.A process according to any one of claims 1 to 11 wherein steady state
reaction conditions prevail in the or the separate reaction zone with
respect to the reactions between compound (3) and the alkali metal or
alkaline earth metal amide base, alkyl lithium or Grignard reagent
and/or between compounds (4) and (5).
13. A process according to any one of claims 1 to 12 wherein R1 is a nitrile
group or a chlorine atom.
-20-

14. A process according to any one of claims 1 to 13 wherein R is tertiary
butyl.
15.A process according to any one of claims 1 to 14 wherein R1 is a
substituted methyl group.
16.A process according to any one of claims 1 to 15 wherein X is lithium
and the alkali metal or alkaline earth metal amide base is a lithium
amide base.
17. A process for the preparation of compound (7):
<IMG>
comprising obtaining compound (6) by the process of any one of
claims 1 to 16 and subjecting that compound to reducing
conditions to obtain compound (7).
18.A process according to claim 17 wherein the reducing conditions are at
least partially provided by one or more enzymes.
19. A process for the preparation of compound (8):
-21-

<IMG>
comprising obtaining compound (7) by the process of claim 17 or
claim 18 and subjecting that compound to acetalising conditions in
the presence of an acid catalyst to obtain compound (8).
20.A process for the preparation of compound (8) according to claim 19
and further converting compound (8) into a useful pharmaceutical
compound.
-22-

Description

CA 02780027 2012-05-04
WO 2011/048425 PCT/GB2010/051778
CONTINUOUS PROCESS FOR THE PRODUCTION OF
BETA-KETO ESTERS BY CLAISEN CONDENSATION
The present invention concerns a process for the production of certain
pharmaceutically useful intermediate compounds, in particular (5R)-1,1-
dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate.
(5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate is a useful
pharmaceutical intermediate particularly in the manufacture of statin drugs
such as atorvastatin, sold under the trade name LipitorTM.
to
(5R)-1,1-dimethylethyl-6-cyano-5-hydroxy-3-oxo-hexanoate is conventionally
manufactured batchwise by a Claisen type reaction between tertiary butyl
acetate (strictly speaking, the enolate of tertiary butyl acetate) and (3R)-4-
cyano-3-hydroxybutyric acid, ethyl ester. However, the enolate is unstable
above -30 C. At 0-5 C in THE at concentrations of about 1.5M the
compound begins to decompose in less than 1 minute and is substantially
decomposed in around 5 mins.
Decomposition of the enolate can take place in accordance with the following
scheme:
-1-

CA 02780027 2012-05-04
WO 2011/048425 PCT/GB2010/051778
OBut 0
11
'~-OU (C + LiOBut
TBA ketene
Y
O OLi HX O O
,---
OBut
OBut + LiX
LiOBut
Tertiary butyl acetate enolate (TBA in the above scheme) decomposes to the
ketene which then reacts with another molecule of tert-butyl acetate enolate
to
self condense to give tert-butylacetoacetate. tert-Butylacetoacetate is the
major impurity in all Claisen type reactions involving TBA. Since the reagents
that go to make tert-butyl acetate enolate, in particular the lithium amide
base,
are expensive, the formation of tert-butylacetoacetate is a costly
inefficiency.
As batching operations/heat transfer takes hours not minutes at industrial
scale it is thus necessary in order to prepare and use the enolate to utilise
reactor temperatures as low as -30 C or lower (as taught in EP-A-0643689).
Thus, conventionally, cryogenic reactors are required for good reagent
efficiency and yield to be obtained.
It has been suggested, for example in US 6,903,225 and in US 6,340,767, to
use higher temperatures, but these disclosures appear to address the
problem of enolate self-condensation by forming the enolate very slowly by
dropwise addition of base to acetate over a three hour period and by carrying
out the enolate formation reaction in the presence of the other reaction
partner
4-chloro-3-hydroxybutyric acid ethyl ester, conditions which are seemingly
-2-

CA 02780027 2012-05-04
WO 2011/048425 PCT/GB2010/051778
unlikely to be commercially attractive on an industrial scale. Another
apparent
disadvantage of this process is that in some cases it may not be possible to
carry out the enolisation reaction in the presence of the other reaction
partner,
particularly if this reaction partner is sensitive to the strong bases such as
lithium amides that are used for such enolisations.
It is an object of the present invention to address these problems.
According to the present invention there is provided a continuous process for
the production of compounds having the general formula (6):
R2 O O
R OR
3 R3 (6)
wherein:
R is a straight or branched chain alkyl group;
R1 is a straight or branched chain alkyl group substituted
with a nitrite group, a hydroxy group or a halogen atom;
R2 is a hydroxy group or a keto group; and
each R3 is, independently, hydrogen or a straight or
branched chain alkyl group,
the process comprising providing to a reaction zone a continuous
stream of a compound of formula (3):
-3-

CA 02780027 2012-05-04
WO 2011/048425 PCT/GB2010/051778
R4 0
~OR
R3 ......(3)
wherein R and R3 are as previously defined and R4 is
hydrogen or has the general formula (7):
Off
R3 .......(7)
wherein R3 is as defined above
and a continuous stream of an alkali metal or alkaline earth metal
amide base, alkyl lithium or Grignard reagent; contacting the
continuous streams together in the reaction zone to yield the
enolate of formula (4):
Ox
R
OR
R3 ......(4)
wherein R and R3 are as previously defined, X is an alkali metal or
alkaline earth metal, and R5 is hydrogen or has the general
formula (8):
Ox
R3 .......($)
wherein R3 and X are as previously defined;
-4-

CA 02780027 2012-05-04
WO 2011/048425 PCT/GB2010/051778
providing to the or a separate reaction zone a continuous stream
of a compound of formula (5):
R6 0
R1 OR
n ......(5)
wherein R and R1 are as previously defined or together define a
ring structure, R6 is hydrogen, hydroxyl, alkoxyl or a keto group
and n isO or 1;
and contacting the continuous stream of compound (5) with a
continuous stream of the enolate (4) in the or the separate
reaction zone at a temperature above 20 C to yield a compound
of formula (1):
Ox Ox
R1r' oR......(1)
wherein R1, R and X are as previously defined, and treating the
compound of formula (1) with an acid to yield the compound of
formula (6).
We have found that by conducting this Claisen type reaction under continuous
conditions, it is possible to operate the process at significantly higher
-5-

CA 02780027 2012-05-04
WO 2011/048425 PCT/GB2010/051778
temperatures than have hitherto been considered workable, whilst obtaining
good yields and purity. As a consequence, the process of the invention does
not require cryogenic cooling equipment, and provides the compound (6)
product in good yields and purities, notwithstanding the relatively high
temperature of operation.
Conventionally, enolates of the type represented by formula (4) are prepared
at low temperature due to their thermal instability. For similar reasons, the
reaction between compound (4) and compound (5) also conventionally takes
place at low temperature. This is because on an industrial scale if one
prepares an 8000L batch of enolate mixture at -60 C and one wants to carry
out a subsequent reaction at 10 C using this enolate solution it is not
possible
to warm this solution to 10 C at a rate faster than the enolate will
decompose.
Lying behind the present invention is the realisation that it is possible
prepare
the enolate at a higher than conventional temperature and use it immediately
also at a higher than conventional temperature. In the context of a continuous
process which allows the operator very rapidly (preferably over a time frame
of minutes or seconds) to mix the enolate with a reaction partner (compound
(5)). In the continuous process of the invention the enolate is enabled to
react
with its reaction partner (for example 4-cyano-3-hydroxybutyric acid ethyl
ester) at a faster rate than it would decompose (self-condense). A significant
advantage of the inventive process is therefore that it allows the use of non-
cryogenic conditions in both the synthesis and use of ester enolates, and also
for rapid production of compound (6) on an industrial scale.
-6-

CA 02780027 2012-05-04
WO 2011/048425 PCT/GB2010/051778
Preferably in the process of the invention, the enolisation reaction is
conducted at least partially before contacting the enol compound (4) with its
reaction partner compound (5). In other words, preferably the steps of
providing to the reaction zone a continuous stream of a compound of formula
(3) and a continuous stream of an alkali metal or alkaline earth metal amide
base, alkyl lithium or a Grignard reagent, and the steps of providing to the
or
the separate reaction zone a continuous stream of a compound of formula (5)
are sequential steps in the process of the invention. This aspect of the
invention is found to be particularly advantageous when compound (5) is itself
unstable in the presence of the alkali metal or alkaline earth metal amide
base, alkyl lithium or a Grignard reagent, as appears to be the case for
example when R1 contains a nitrite group.
We have found that under the continuous operating conditions of the process
of the invention it is also possible to reduce the stoichiometric ratio of
alkali
metal or alkaline earth metal amide base, alkyl lithium or a Grignard reagent
to compound of formula (5) below the level conventionally employed, an
important advantage given the expense and/or difficulty of manufacturing the
alkali metal or alkaline earth metal amide base, alkyl lithium or Grignard
reagent.
Accordingly, in one preferred process according to the invention, the
stoichiometric ratio of alkali metal or alkaline earth metal amide base, alkyl
lithium or a Grignard reagent to compound (5) supplied to the and/or to the
-7-

CA 02780027 2012-05-04
WO 2011/048425 PCT/GB2010/051778
separate reaction zone is less than about 4.5 : 1, more preferably less than
about 4.0 : 1 and most preferably less than about 3.5 : 1.
Continuous flow production of the unstable compound (4) allows the
compound to be used as it is formed, and allows the use of very high
heat/mass transfer flow equipment, permitting excellent temperature control of
the reaction mixture.
Consequently, the synthesis and use of compound (4) may be effected in the
process of the invention at higher temperatures than typically observed for
batch type reactor systems.
Preferably the temperature at which compounds (4) and (5) are reacted
together is above 25 C, more preferably above 30 C.
A significant advantage of using a relatively high temperature in the reaction
between compounds (4) and (5) is that only a low residence time in the or the
separate reaction zone need be employed.
Preferably the residence time of the contacted continuous streams of
compounds (4) and (5) in the or the separate reaction zone is less than about
5 minutes, more preferably less than about I minute, still more preferably
less
than about 50 seconds and most preferably less than about 40, or even 30
seconds.
-8-

CA 02780027 2012-05-04
WO 2011/048425 PCT/GB2010/051778
Preferably the residence time of the contacted continuous streams of
compound (3) and the alkali metal or alkaline earth metal amide base, alkyl
lithium or Grignard reagent in the reaction zone is less than about 5 minutes,
more preferably less than about 4 minutes, still more preferably less than
about 3 minutes and most preferably less than about 2 minutes.
Preferably the enolate compound (4) is prepared from the reaction of
compound (3) and the alkali metal or alkaline earth metal amide base, alkyl
lithium or Grignard reagent in a first reaction zone, and the compound of
formula (1) is prepared from the reaction between compounds (4) and (5) in a
second reaction zone. We have found using separate reaction zones to be
preferable in terms of yield and/or purity, particularly when R1 contains a
nitrile
group, compound (6) tending to have a red colouration due to impurities when
the same reaction zone is used for both reactions. However, the use of first
and second reaction zones is preferable rather than essential in the process
of the invention and, particularly when R1 contains a halogen atom, does not
appear to compromise purity of the product unduly.
The treatment of compound (1) with acid may take place in the same or a
different reaction zone as that in which the reaction between compounds (4)
and (5) takes place, and this step of the process need not be continuous,
although it can be.
By "continuous" is preferably meant that steady state reaction conditions
prevail in the or the separate reaction zone as far as the reactions between
-9-

CA 02780027 2012-05-04
WO 2011/048425 PCT/GB2010/051778
compound (3) and the alkali metal or alkaline earth metal amide base, alkyl
lithium or Grignard reagent and/or between compounds (4) and (5) are
concerned. However reagent streams may be supplied to the or the separate
reaction zone, and product stream(s) may be recovered therefrom as
consistent continuous streams or as intermittent or pulsed streams.
R1 is preferably a substituted methyl group. When R1 is substituted with a
halogen atom, the halogen atom is preferably chlorine.
R is preferably tertiary butyl.
X is preferably lithium and the alkali metal or alkaline earth metal amide
base
is preferably a lithium amide base, such as lithium hexamethyldisilazane or
lithium diiospropylamide, lithium dicyclohexylamide or lithium amide.
Preferred processes in accordance with the invention for the preparation of
particular compounds (6) in accordance with the process of the invention are
summarised in the following Table 1 wherein each particularly preferred
starting material (3) is shown in the first column, each alkali metal or
alkaline
earth metal amide base, alkyl lithium or Grignard reagent (indicated by the
word "base") is shown in the second column, each resulting enolate (4) is
shown in the third column, each reaction partner (5) is shown in the fourth
column and each target compound (6) is shown in the fifth column:
Table 1
-10-

CA 02780027 2012-05-04
WO 2011/048425 PCT/GB2010/051778
(3) (base) (4) (5) (6)
0
o c 0Li OL 0 0 0
2UHMDS Me CI
06u C78ut ~'Y 8ut
OH 0
0 OU CI `~ ~ OH 0 0
LDA oEt
CI lo. "'~OBUt OBut OBut
OH 0
0 OLi NC OH 0 0 ~'~
/' II LiHMD10 5 %~ oEc
J.~ NC
5 OBut OBut OBut
RO
O LiHMDS OLi O O OR 0 0
_ OBut
~Oeut '~-OBut HO
Where stereochemistry is specified in the table above, it should be understood
10 that the process of the invention is also directed towards all
stereoisomers
and enantiomers.
Also provided in accordance with the present invention is a process for the
preparation of compound (7):
OH OH 0
R1 OR .......(7)
-11-

CA 02780027 2012-05-04
WO 2011/048425 PCT/GB2010/051778
comprising obtaining compound (6) by the aforementioned process and
subjecting that compound to reducing conditions to obtain compound (7).
Preferably the reducing conditions are at least partially provided by one or
more enzymes.
Also provided in accordance with the invention is a process for the
preparation
of compound (8):
0 0 0
.......(8)
comprising obtaining compound (7) by the aforementioned process and
subjecting that compound to acetalising conditions in the presence of an acid
catalyst to obtain compound (8).
The invention also provides a process for the preparation of compound (8) as
aforesaid and further converting compound (8) into a useful pharmaceutical
compound.
The invention will now be more particularly described with reference to the
following example.
Example
-12-

CA 02780027 2012-05-04
WO 2011/048425 PCT/GB2010/051778
Synthetic Sequence
/ Si(Me)3 0 OBut /Si(Me)3
LiN + t 0 C + HN
Si(Me)3 OBu residence time 25-40 secs OLi Si(Me)3
40-50 C NC~0
residence time 2 2-8 secs OR
OH 0 0 OLi OLi 0
NC OBut NC OBut
HCI aq
Preparation of tert-butyl acetate enolate
t-Butyl Acetate enolate was prepared by pumping two solutions through a
1.016mm i.d. stainless steel capillary tube:
1. A solution of lithium hexamethyldisilazane (24.36% w/w in THF) at a
flow rate of 53.02 ml/min
2. A solution of tent-butyl acetate (50% w/w in THF) at a flow rate of 19.77
ml/min.
This gave very rapid and intimate mixing of the two solutions and a residence
time for the reaction of 26.5secs. The reaction temperature was controlled by
submerging the entire capillary reactor in a Huber heater/ chiller unit with a
set-point of 0 C.
Preparation of (R)-6-Cyano-5-hydroxy-3-oxo-hexanoic acid tert-butyl
ester
-13-

CA 02780027 2012-05-04
WO 2011/048425 PCT/GB2010/051778
The t-butyl acetate enolate stream was then immediately mixed with a flow of
ethyl (R)-4-cyano-3-hydroxybutyrate (50% w/w in THF) (flow rate of
6.15ml/min) and reacted in another stainless steel 1.016mm i.d. capillary tube
for a residence time of 2.4secs. This gave very rapid and intimate mixing of
the two solutions. The reaction temperature was controlled by submerging
the entire capillary reactor in a water bath with a set-point of 55 C. The
product stream was then cooled prior to quench by flowing through a 1.76mm
i.d. stainless steel capillary tube where the reaction temperature was
controlled by submerging the reactor in an ice/water bath for a residence time
of 3.6secs.
Reaction quench/work-up
This mixture was then quenched into hydrochloric acid solution (1.7Lts, 10%
w/w) in a jacketed stirred glass reactor where the temperature was maintained
at X25 C using Huber heater/ chiller unit. The pH was not allowed to rise
above 2. Upon completion the agitator was stopped and the reaction mixture
was allowed to separate, and the lower aqueous layer was split (3650g), and
extracted with dichloromethane (2 x 250ml). The upper organic layer (3683g)
was combined with the organic extracts, and washed with water (2 x 250ml).
The organic extract was concentrated via a rotary film evaporator (bath temp
35 C) to give crude (R)-6-Cyano-5-hydroxy-3-oxo-hexanoic acid tert-butyl
ester (304.3g) as a yellow/brown oil. The yield for the reaction was 72% as
determined by 1HNMR analysis using tridecane as internal standard.
-14-

CA 02780027 2012-05-04
WO 2011/048425 PCT/GB2010/051778
(1HNMR analysis procedure: a 10sec sample of unquenched product stream
was added to a mixture of dichloromethane (5ml), tridecane (450pl) and
hydrochloric acid (10% w/w, 5ml). After briefly shaking, the mixture was
allowed to separate and the lower organic layer was split and dried over
magnesium sulphate. The sample was concentrated using a nitrogen sparge
to give an oil, which was diluted with CDCI3 and analysed).
This example is intended only to illustrate the invention, which is more
particularly defined in the claims which follow.
-15-

Representative Drawing